Therapy-related myelodysplasia (t-MDS) is a lethal complication of genotoxic cancer therapy and is observed at a high frequency in Hodgkins lymphoma (HL) and non-Hodgkins lymphoma (NHL) patients treated with autologous hematopoietic cell transplant (HCT) However mechanisms of susceptibility to and the sequence of cellular and molecular abnormalities leading to t-MDS are unknown. To investigate the pathogenesis of t-MDS we are conducting a prospective, longitudinal evaluation of a cohort of NHL and HL patients undergoing HCT at our center. Blood and marrow samples are being collected and banked pre-HCT and sequentially post-HCT for up to 5 years. In this application we propose to investigate alterations in gene expression patterns and genetic variance in hematopoietic cells associated with development of t-MDS. We will use a nested case control design to compare patients within the cohort who develop t-MDS with matched controls that do not develop t-MDS. This study design allows for serial assessment of molecular abnormalities leading to the development of MDS in a high-risk population. We will perform genome-wide gene expression profiling using microarrays to identify alterations in gene expression in hematopoietic cells from pre-HCT and sequential post-HCT samples associated with development of t-MDS (Specific Aim 1). SNP arrays will be used to analyze the interaction between genetic variations and therapeutic factors and development of t-MDS, and for genome-wide screening for copy number abnormalities and loss of heterozygosity to study serial acquisitions of genetic lesions in hematopoietic cells from patients developing t-MDS (Specific Aim 2). Samples will also be assayed for specific genetic lesions known to be associated with MDS. We will examine the relationship between observed genetic lesions and altered gene expression patterns. Gene expression and genetic data will be analyzed for alterations in pathways and gene networks that regulate DNA damage response and hematopoietic growth, and molecular abnormalities will be correlated with functional defects in these mechanisms (Specific Aim 3). These studies will provide important insights into critical molecular mechanisms underlying development of t-MDS, and may identify potential targets for preventive and therapeutic strategies. These studies may also allow identification of markers of susceptibility to t-MDS allowing early detection of patients at risk for this complication.